EP2528925B1 - THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON PROTEIN KINASES - Google Patents

THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON PROTEIN KINASES Download PDF

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Publication number
EP2528925B1
EP2528925B1 EP11737323.3A EP11737323A EP2528925B1 EP 2528925 B1 EP2528925 B1 EP 2528925B1 EP 11737323 A EP11737323 A EP 11737323A EP 2528925 B1 EP2528925 B1 EP 2528925B1
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Prior art keywords
pyrimidine
thieno
methyl
trifluoromethyl
carboxamide
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EP11737323.3A
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German (de)
English (en)
French (fr)
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EP2528925A2 (en
EP2528925A4 (en
Inventor
Jung Beom Son
Seung Hyun Jung
Wha Il Choi
Young Hee Jung
Jae Yul Choi
Ji Yeon Song
Kyu Hang Lee
Jae Chul Lee
Eun Young Kim
Young Gil Ahn
Maeng Sup Kim
Hwan Geun Choi
Tae Bo Sim
Young Jin Ham
Dong-Sik Park
Hwan Kim
Dong-Wook Kim
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Korea Advanced Institute of Science and Technology KAIST
Korea Institute of Science and Technology KIST
Industry Academic Cooperation Foundation of Catholic University of Korea
Hanmi Science Co Ltd
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Korea Advanced Institute of Science and Technology KAIST
Korea Institute of Science and Technology KIST
Industry Academic Cooperation Foundation of Catholic University of Korea
Hanmi Science Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel thieno[3,2-d]pyrimidine derivatives having inhibitory activity on protein kinases and a pharmaceutical composition for preventing or treating abnormal cell growth diseases.
  • Protein kinases a catalyst enzyme for phosphorylation of hydroxyl groups in tyrosine, serine and threonine moieties of protein, play an important role in a growth factor signal transduction inducing growth, differentiation and proliferation on cells.
  • a signal transduction system in body should keep a balance between on and off.
  • a mutation or an overexpression of particular protein kinases collapses the signal transduction system in a normal cell, e.g., by a continuous signal transduction in body, to induce various diseases such as cancer, inflammation, metabolic disease, and brain disease.
  • Human protein kinases are estimated to exist in 518 species, about 1.7% of human whole genes ( Manning et al., Science, 2002, 298, 1912 ), and largely divided into tyrosine protein kinases (at least 90 species) and serine/threonine protein kinases.
  • Tyrosine protein kinases may be divided into receptor tyrosine kinases which are classified into 20 subtypes of 58 species and cytoplasm/non-receptors which are classified into 10 subtypes of 32 species.
  • Receptor tyrosine kinases have domains on the cell surface for reception of growth factors, and active sites in the cytoplasm for phosphorylation of tyrosine moieties.
  • a growth factor binds to the growth factors receptor site on the cell surface of the receptor tyrosine kinase
  • the receptor tyrosine kinase forms a polymer and the tyrosine moieties of cytoplasm are autophosphorylated.
  • the signal transduction progresses inside nuclear by sequential phosphorylation of subfamily proteins, and finally, transcription factors inducing cancer are overexpressed.
  • the Bcr-Abl chromosome translocation is called Philadelphia chromosome ( Nowell and Hungerford, J. Natl. Cancer Inst., 1960;25:85 ).
  • the Bcr part has oligomerization domains and the Abl part has tyrosine kinase domains.
  • the size of the Bcr-Abl gene is determined by the cut position of the Bcr gene, and 3 subtypes (190, 210, 230 kDa) of Bcr-Abl genes have been reported.
  • the Bcr-Abl gene is a leukemia-inducing factor, particularly p210-Bcr-Abl is a direct tumor factor inducing chronic myeloid leukemia (CML).
  • CML chronic myeloid leukemia
  • the correlation between p210-Bcr-Abl and the CML induction is very high (>98%).
  • Novartis developed Gleevec (imatinib mesylate) which can selectively inhibit Bcr-Abl, i.e., by inhibiting tyrosine kinases of Abl, and released in 2002.
  • Gleevec the first targeted antitumor agent
  • inactivation of Gleevec by the acquired resistance became a problem.
  • the most important factor among various factors inducing the acquired resistance is point-mutation generated in the Abl kinase domains.
  • Nilotinib and dasatinib which are recently available, effectively inhibit many point-mutant species generated by the acquired Gleevec-resistance in Abl kinase domains.
  • T315I-Bcr-Abl mutant species wherein threonine 315 as a gatekeeper of Abl kinase is substituted with isoleucine.
  • nilotinib and dasatinib are unable to inhibit T315I-Bcr-Abl mutant species. Accordingly, there are many attempts to develop a medicine inhibiting T315I-Bcr-Abl mutant species.
  • a vascular endothelial growth factors receptor (VEGFR) of a receptor tyrosine kinase (RTK) is an important modulator for angiogenesis. It is involved in generations of vascular and lymphatic vessel and in homeostasis as well as has an important effect on nerve cells.
  • Vascular endothelial growth factors (VEGF) are predominantly produced by vascular endothelial, hematopoietic and stromal cells in response to hypoxia and upon stimulation with growth factors such as TGFs, interleukins or PDGF.
  • VEGFs bind to VEGF receptor (VEGFR)-1, -2, and -3, and each VEGF isoform binds to a particular subset of these receptors giving rise to the formation of receptor homo- and heterodimers that activate discrete signaling pathways.
  • Signal specificity of VEGF receptors is further modulated upon recruitment of coreceptors, such as neuropilins, heparan sulfate, integrins or cadherins.
  • VEGFR-1 Flt-1
  • VEGFR-2 KDR/Flk-1
  • VEGFR-3 Flt-4
  • VEGFRs are closely related to Fms, Kit and PDGFRs
  • VEGF bind to each specific receptor
  • VEGF-A binds to VEGFR-1 and -2 and to receptor heterodimers
  • VEGF-C and -D bind VEGFR-2 and -3.
  • P1GF and VEGF-B exclusively bind VEGFR-1 and VEGF-E interacts only with VEGFR-2.
  • VEGF-F variants interact with either VEGFR-1 or -2.
  • VEGF-A, -B and P1GF are predominantly required for blood vessel formation, while VEGF-C and -D are essential for the formation of lymphatic vessels.
  • Angiogenesis provides tumors with nutrients, oxygen, and path for cancer cell spread so as to be essential for proliferation and spread.
  • Angiogenesis in normal body is balanced by co-regulation of angiogenic stimulators and angiogenic suppressors, while in off-balanced cancer cells VEGFR is activated by growth factors (VEGF) which have a great effect on vascular endothelial cells.
  • VEGF growth factors
  • VEGF receptor tyrosine kinases using low molecular synthetic materials are being developed, most of which are able to be used for solid tumors and to inhibit angiogenesis activated only in cancer cells and have an excellent medicinal effect with relatively low side effects.
  • Tie2 a kind of receptor tyrosine kinase, is deeply concerned with angiogenesis and vasculature.
  • the domain structure of Tie2 is conserved in all vertebrates very well ( Lyons et al., Isolation of the zebrafish homologues for the tie-1 and tie-2 endothelium-specific receptor tyrosine kinases., Dev Dyn., 1998; 212:133-140 ).
  • Tie2 ligands are angiopoietins (Ang). Ang2 does not induce Tie2 autophosphorylation and disturbs Tie2 activation induced by Angl.
  • PI3K-Akt activation In endothelial cells, Tie2 activation by Ang2 induces PI3K-Akt activation ( Jones et al., Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration., J Biol Chem., 1999; 274:3089630905 ).
  • mitogen-activated protein kinases (MAPK) signal transduction path as main signal transduction system of Tie2, adapter protein GRB2 and protein tyrosine phosphatase SHP2 play an important role in dimerization process by autophosphorylation of Tie2 receptor tyrosine kinases.
  • MAPK mitogen-activated protein kinases
  • Ang/Tie2 and vascular endothelial growth factors (VEGF) signal transduction path perform an important function in angiogenesis of cancer cells.
  • Tie2 is manifested in vascular endothelial, particularly in the infiltration area of cancer cells.
  • Tie2 overexpressions are found in breast cancer ( Peters et al., Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis. Br J Cancer, 1998; 77:5156 ) and also in uterine cancer, liver cancer, and brain cancer.
  • RET receptor tyrosine kinases
  • N-terminal intermolecular domains of RET consist of 4 N-cadherin-like repeats, calcium-binding sites, 9 N-glycosylation sites, and cysteine-rich regions ( Aiaksinen et al., Nat. Rev. Neurosci., 2002;3:383 ).
  • the cytoplasm area of RET has at least 12 tyrosine autophosphorylation sites ( Liu, J., Biol. Chem., 1996;271:5309 ).
  • RET9 variants have 16 autophosphorylation sites in the kinase domain.
  • GFL glial-derived neurotropic factor-family ligands
  • GFR-alpha having 4 subtypes of GFR-alpha1-4 is known as glycosylphosphatidylinositol-anchored co-receptor.
  • RET plays an important role in parasympathetic, enteric nervous systems, and kidney generation of mouse ( Pachnis et al., Development, 1993;119:1005 ).
  • RET defunctionalization by germline mutation induce Hirschsprung's disease which is identified as a congenitial aganglionosis of distal intestines ( Manie et al., Trends Genet., 2001;17:580 ).
  • mutations promoting the function of RET induce MEN2A (multiple endocrine neoplasia type 2A), MEN2B, and familial medullary thyroid carcinoma (FMTC).
  • MEN2A multiple endocrine neoplasia type 2A
  • MEN2B familial medullary thyroid carcinoma
  • FMTC familial medullary thyroid carcinoma
  • RET is proved to be a promising molecular target for development of a medicine of thyroid cancer ( Cote and Gagel, N. Engl. J. Med., 2003;349
  • a pharmaceutical composition for preventing or treating abnormal cell growth diseases resulted from overexpression of a protein kinase comprising the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the inventive thieno[3,2-d]pyrimidine derivatives, or a pharmaceutically acceptable salt, hydrate or solvate thereof has an excellent inhibitory activity on protein kinases, and a pharmaceutical composition comprising the same is effective in preventing or treating abnormal cell growth diseases.
  • the aryl is phenyl; and heterocycloalkyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or diazepanyl, wherein said aryl, and heterocycloalkyl are each independently unsubstituted or substituted by C 1-6 alkyl, halogen, diC 1-6 alkylamino or C 1-6 alkoxy.
  • Z is preferably H, methyl, ethyl, 2-hydroxyethyl, 2-morpholinoethyl, isopropyl, cyclopropyl, cyclopentyl, cyclopropylcarbonyl, benzoyl, phenyl, 4-methoxyphenyl, 4-(4-methylpiperidine-1-yl)phenyl, 4-(4-ethylpiperazin-1-yl)phenyl, pyridine-4-yl, pyridine-2-yl, 5-methylpyridine-2-yl, or 6-methylpyridine-3-yl.
  • Preferable compound according to the present invention is a thieno[3,2-d]pyrimidine derivative selected from the group consisting of:
  • the starting material or intermediate may be the compounds of formulas (II) to (V): wherein,
  • inventive compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof exhibits an excellent inhibitory activity on protein kinases.
  • the present invention provides a pharmaceutical composition for preventing or treating abnormal cell growth diseases resulted from overexpression of a protein kinase, comprising the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
  • the protein kinase may comprise Bcr-Abl, FGFR, Flt, KDR, PDGFR, Fms, Kit, Raf, Tie2, Src, and Ret.
  • the pharmaceutical composition of the present invention has an excellent inhibitory activity on these kinases.
  • the abnormal cell growth disease may comprise stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestinal cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, uterine cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, renal cancer, sarcoma, prostate cancer, urethra cancer, bladder cancer, blood cancer, lymphoma, psoriasis and fibroadenoma.
  • the blood cancer may be leukemia, multiple myeloma or myelodysplastic syndrome; and the lymphoma may be Hodgkin's disease or non-Hodgkin's lymphoma.
  • the present disclosure provides a method for preventing or treating abnormal cell growth diseases resulted from overexpression of a protein kinase, comprising administering the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof to a subject requiring prevention or treatment of abnormal cell growth diseases resulted from overexpression of a protein kinase.
  • a proposed daily dose of the inventive compound for administration to a human may be in the range of 1 mg/day to 2,000 mg/day.
  • the inventive compound may be administered in a single dose or in divided doses per day. It is understood that the daily dose should be determined in light of various relevant factors including the condition, age, body weight and sex of the subject to be treated, administration route, and disease severity; and, therefore, the dosage suggested above should not be construed to limit the scope of the present invention in anyway.
  • the present invention provides thieno[3,2-d]pyrimidine derivatives represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt should have a low toxicity in human and should not adversely affect the biological activity and physicochemical properties of the parent compound.
  • the pharmaceutically acceptable salts comprise an acid addition salt of a pharmaceutically acceptable free acid and a base compound of formula (I); an alkali metal salt (e.g., sodium salt) and an alkaline earth metal salt (e.g., calcium salt); an organic base addition salt of an organic base and a carboxylic acid compound of formula (I); and an amino acid addition salt.
  • Preferable salt forms of inventive compound comprise a salt formed with an inorganic acid or an organic acid.
  • the inorganic acid are hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and bromic acid.
  • the organic acid are acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, malic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, maleic acid, oxalic acid, benzoic acid, aspartic acid, and glutamic acid.
  • the organic base addition salt may be prepared using an organic base such as tris(hydroxymethyl)methylamine and dicyclohexylamine.
  • the amino acid addition salt may be prepared using a natural amino acid such as alanine and glycine.
  • salts may be prepared in a conventional manner.
  • the salts may be prepared by dissolving the compound of formula (I) in a water-miscible solvent such as methanol, ethanol, acetone and 1,4-dioxane; adding a free acid or free base thereto; and then crystallizing.
  • composition of the present invention comprising the bicyclic heteroaryl derivatives represented by formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient, may further contain a conventional nontoxic pharmaceutically acceptable carrier, a reinforcing agent, or a diluent, to be formulated for parenteral administration or oral administration, e.g., in the form of a tablet, capsule, troches, solution or suspension.
  • a conventional nontoxic pharmaceutically acceptable carrier e.g., a reinforcing agent, or a diluent
  • the pharmaceutical composition of the present invention may comprise conventional additives such as a diluent, a sweetener, a binder, a solubilizing agent, a solubilizing co-agent, a wetting agent, an emulsifier, an isoosmotic agent, an absorbent, a disintegrator, an antioxidant, a preservative, a lubricant, a filler, and an aromatics.
  • a diluent such as a diluent, a sweetener, a binder, a solubilizing agent, a solubilizing co-agent, a wetting agent, an emulsifier, an isoosmotic agent, an absorbent, a disintegrator, an antioxidant, a preservative, a lubricant, a filler, and an aromatics.
  • additives examples include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinyl pyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla essence, etc.
  • Examples of the carrier employed in the injectable composition of the present invention are distilled water, a saline solution, a glucose solution, a glucose-like solution, alcohol, glycol ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, a surfactant, a suspension agent and an emulsifier.
  • glycol ether e.g., polyethylene glycol 400
  • Methyl-3-aminothiophene-2-carboxylate (15g, 98.57mmol) (Matrix, Cat # 018289, CAS [22288-78-4]) was dissolved in formamide (50mL), and the mixture was stirred at 180°C for 5 hours. The reaction mixture was further stirred at room temperature for 2 hours and then filtered to obtain the title compound.
  • the aqueous layer was separated from the organic layer and extracted with ethyl acetate.
  • the combined organic layer was dried with MgSO 4 and concentrated.
  • Step 4 (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid
  • Step 5 (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid and 4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid and 3-(4-ethylpiperazine-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
  • Step 3 of Example 1 The procedure of Step 3 of Example 1 was repeated except for using 2-iodo-1-methyl-4-nitrobenzene (TCI Laboratory Chemicals, Cat. # I0706, CAS [7745-92-8]) instead of ethyl-3-iodo-4-methyl benzoate to obtain the title compound.
  • 2-iodo-1-methyl-4-nitrobenzene TCI Laboratory Chemicals, Cat. # I0706, CAS [7745-92-8]
  • Step 3 of Example 4 The procedure of Step 3 of Example 4 was repeated except for using 4-(1-methylpiperidine-4-yloxy)-3-(trifluoromethyl)benzoic acid instead of 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzoic acid to obtain the title compound (see Table 1).
  • Step 3 of Example 4 The procedure of Step 3 of Example 4 was repeated except for using 4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzoic acid instead of 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzoic acid to obtain the title compound (see Table 1).
  • Step 2 of Example 1 was repeated except for using 7-bromo-4-(methylthio)thieno[3,2-d]pyrimidine (500mg, 1.92mmol) obtained in Step 4 of Preparation Example 1 to obtain the title compound.
  • NaH 2 PO 4 ⁇ 2H 2 O (513mg, 3.29mmol) was dissolved in water (2mL) and then 4-(methylthio)thieno[3,2-d]pyrimidine-7-carbaldehyde (300mg, 1.68mmol) dissolved in acetone (3mL) and DMSO (3mL) was added thereto at 0°C.
  • NaClO 2 (194mg, 2.15mmol) dissolved in water (2mL) was added at the same temperature to the reaction mixture, which was stirred for 2 hours. After the reaction was completed water (10mL) was further added to the reaction mixture, which was stirred for 2 hours and filtered to obtain a solid. The solid was washed with water several times and dried with N 2 gas to obtain the title compound as a white solid.
  • Step 1 of Example 1 was repeated except for using the compound obtained in Step 2 of Example 8 to obtain the title compound.
  • Step 4 of Example 1 was repeated except for using the compound obtained in Step 3 of Example 8 to obtain the title compound.
  • Step 5 4-Amino-N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • Step 5 of Example 1 was repeated except for using the compound obtained in Step 4 of Example 8 to obtain the title compound.
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3-methoxyaniline to obtain the title compound (see Table 1).
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzenamine to obtain the title compound (see Table 1).
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3,5-dimethoxyaniline to obtain the title compound (see Table 1).
  • Step 1 N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)-4-(methylthio)thieno[3,2-d]pyrimidine-7-carboxamide
  • Step 1 of Example 8 was repeated except for using the compound obtained in Preparation Example 2 and 3-amino-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide to obtain the title compound.
  • Step 2 N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)-4-(methylsulfinyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • Step 2 of Example 8 was repeated except for using the compound obtained in Step 1 of Example 13 to obtain the title compound.
  • Step 3 4-(4-Methoxyphenylamino)-N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)-4-(methylsulfinyl)thieno[3,2-d]pyrimidine-7-carboxamide (30mg, 0.060mmol) was dissolved in dioxane (1mL) and DIPEA (20 ⁇ L, 0.119mmol) and 4-methoxybenzeneamine (37mg, 0.298mmol) were added thereto. The reaction mixture was stirred at 120°C for 18 hours, cooled to room temperature, dilluted with ethyl acetate and washed with a brine. The organic layer was dried with MgSO 4 , filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography to obtain the title compound (28mg, 81% yield).
  • Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 3,4,5-trimethoxyaniline to obtain the title compound (see Table 1).
  • Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 6-methylpyridine-3-amine to obtain the title compound (see Table 1).
  • Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 4-(4-ethylpiperazine-1-yl)aniline to obtain the title compound (see Table 1).
  • Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and isopropylamine to obtain the title compound (see Table 1).
  • Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and methylamine hydrochloride to obtain the title compound (see Table 1).
  • Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 2-aminoethanol to obtain the title compound (see Table 1).
  • Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 2-morpholino ethaneamine to obtain the title compound (see Table 1).
  • Methyl 3-amino-4-methylthiophene-2-carboxylate (3.0g) was added to formamide (5mL), and the mixture was stirred at 200°C for 3 hours. After cooling to room temperature water (50mL) was added thereto and then stirred for 15 hours at room temperature to obtain a solid. The solid was filtered, washed with water and dried with N 2 gas to obtain the title compound as a white solid without further purification.
  • Step 1 of Example 8 The procedure of Step 1 of Example 8 was repeated except for using the compound obtained in Preparation Example 3 as a starting material to obtain the title compound.
  • Step 3 of Example 13 The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 1 of Example 21 as a starting material to obtain the title compound.
  • Step 4 of Example 1 was repeated except for using the compound obtained in Step 2 of Example 21 as a starting material to obtain the title compound.
  • Step 4 4-(Cyclopropylamino)-N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • Step 5 of Example 1 was repeated except for using the compound obtained in Step 3 of Example 21 as a starting material to obtain the title compound.
  • NaH 2 PO 4 .2H 2 O (67g, 429mmol) was dissolved in water (220mL), the compound (41g, 187mmol) obtained in Step 2 of Preparation Example 4 dissolved in a acetone/dimethyl sulfoxide mixture (1:1, v/v) (640mL) was added thereto slowly, cooled to 0°C and stirred for 30 minutes.
  • NaClO 2 (25.3g, 280mmol) dissolved in water (220mL) was added to the reaction mixture slowly at 0°C and stirred at room temperature for 5 hours.
  • Step 4 t-Butyl 4-(1-methylpiperidine-4-yloxy)-3-(trifluoromethyl)phenylcarbamate
  • the reaction mixture was stirred for 1 hours at room temperature, dilluted with ethyl acetate (30mL) and washed with an aqueous sodium hydrogen carbonate solution (30mL).
  • the organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure.
  • the concentrated mixture was filtered with a silica column using ethyl acetate to remove copper impurities, and the filtrate was distilled under reduced pressure.
  • the concentrated mixture was crystallized with ethyl acetate (3mL) and n-hexane (30mL) to obtain the title compound (1.31g) as a bright green solid..
  • Step 2 4-Methyl -N-(3-(2-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)-3-nitrobenzamide
  • Step 3 of Preparation Example 3 was repeated except for using 1-methyl-4-nitro-2-(trifluoromethyl)benzene as a starting material to obtain the title compound.
  • Step 4 of Preparation Example 3 was repeated except for using the compound obtained in Step 1 of Preparation Example 7 as a starting material to obtain the title compound.
  • Step 3 4-Amino-2-(trifluoromethyl)benzyl acetate
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 2 of Preparation Example 7 as a starting material to obtain the title compound.
  • Step 4 4-(4-Methyl-3-nitrobenzamido)-2-(trifluoromethyl)benzyl acetate
  • Step 2 of Preparation Example 6 was repeated except for using the compound obtained in Step 3 of Preparation Example 7 as a starting material to obtain the title compound.
  • Step 5 4-(3-Amino-4-methylbenzamido)-2-(trifluoromethyl)benzyl acetate
  • Step 3 of Preparation Example 6 was repeated except for using the compound obtained in Step 4 of Preparation Example 7 as a starting material to obtain the title compound.
  • Example 22 The procedure of Example 22 was repeated except for using the compound obtained in Preparation Example 7 instead of 3-amino-4-methyl-N-(3-(2-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)benzamide to obtain the title compound.
  • Step 5 of Preparation Example 3 was repeated except for using the compound obtained in Example 23 instead of (4-chlorothieno[3,2-d]pyrimidine-7-yl)methyl acetate to obtain the title compound.
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 3-bromo-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 6-morpholinopyridine-3-amine to obtain the title compound (see Table 1).
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 6-(4-ethylpiperazine-1-yl)pyridine-3-amine to obtain the title compound (see Table 1).
  • Example 22 The procedure of Example 22 was repeated except for using an appropriate starting compound (see Table 1).
  • Example 26 The procedure of Example 26 was repeated except for using an appropriate starting compound (see Table 1).
  • Steps 2 and 3 of Preparation Example 2 was repeated except for using the compound obtained in Step 2 of Example 1 as a starting material to obtain the title compound.
  • Example 8 The procedure of Example 8 was repeated except for using the compound obtained in Step 1 of Example 39 as a starting material to obtain the title compound.
  • Step 4 4-Amino-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • 4-Morpholino-3-(trifluoromethyl)benzoic acid (694mg, 2.523mmol) was dissolved in dimethylformamide (5.6mL), HATU(1.92g, 5.047mmol) and N,N-diisopropylethylamine (1.37mL, 7.851mmol) were added thereto and stirred at room temperature for 30 minutes.
  • 4-Methyl-3-nitroaniline (256mg, 1.682mmol) was added to the reaction mixture and subjected to a reaction at 45°C for 19 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (10mL) and washed with an aqueous sodium hydrogen carbonate solution (10mL).
  • N-(4-methyl-3-nitrophenyl)-4-morpholino-3-(trifluoromethyl)benzoamide (68mg, 0.17mmol) was dissolved in ethanol (1.7mL), tin chloride (190mg, 0.83mmol) was added thereto, and the mixture was subjected to a reaction with reflux for 3 hours.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate and then washed with an aqueous sodium hydrogen carbonate solution.
  • the organic layer was washed with distilled water (10mL x 3), dried with sodium sulfate, and the solvent was distilled under reduced pressure.
  • the concentrated solution was crystallized using ethyl acetate (2mL) and n-hexane (20mL) to obtain the title compound as a bright yellow solid (26mg).
  • Example 82 The compound of Example 82 was prepared according to Reaction Scheme 17 below:
  • Example 82 4-(Cyclopropylamino)-N-(2-methyl-5-(4-(4-methyl-1H-imidazole-1-yl)-3-(trifluoromethyl)benzoamido)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • Step 1 t-Butyl 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylphenylcarbamate
  • Step 3 4-(Cyclopropylamino)-N-(2-methyl-5-(4-(4-methyl-1H-imidazole-1-yl)-3-(trifluoromethyl)benzoamido)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • Step 5 of Example 1 was repeated except for using N-(5-amino-2-methylphenyl)-4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamide and 4-(4-methyl-1H-imidazole-1-yl)-3-(trifluoromethyl)benzoic acid to obtain the title compound.
  • Example 39, 40 or 82 The procedure of Example 39, 40 or 82 was repeated except for using an appropriate starting compound (see Table 1).
  • Example 122 4-Amino-N-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)thieno[3 , 2 - d]pyrimidine - 7 - carboxamide
  • Example 123 4-(Cyclopropylamino)-N-(2-methyl-5-(3-(3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)ureido)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide
  • Example 122 The procedure of Example 122 was repeated except for using the compound obtained in Step 2 of Example 82 instead of N-(5-amino-2-methylphenyl)-4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamide to obtain the title compound.
  • Example 124 The compound of Example 124 was prepared according to Reaction Scheme 17 below:
  • Example 124 3-((4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)benzamide
  • Step 1 4-(Methylthio)-7-((trimethylsilyl)ethynyl)thieno[3,2-d]pyrimidine
  • Step 4 Ethyl 3-((4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)- 4-methyl benzoate
  • Ethyl-4-methyl-3-((4-(methylthio)thieno[3,2-d]pyrimidine-7-yl)ethynyl)benzoate (440mg, 1.19mmol) was dissolved in methylene chloride (6mL) and then m -CPBA (616mg, 3.57mmol) was added thereto at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and methylene chloride (20mL) was added thereto. The reaction mixture was washed with a sat. aqueous NaHCO 3 solution (30mL x 3). The organic layer was dried with MgSO 4 , filtered with Celite and concentrated to obtain the title compound without further purification.
  • Step 5 Ethyl-3-((4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)- 4-methyl benzoate
  • Step 6 3-((4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methylbenzoic acid
  • Step 4 of Example 1 The procedure of Step 4 of Example 1 was repeated except for using the compound obtained in Step 5 of Exmaple 123 as a starting material to obtain the title compound.
  • Step 7 3-((4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)benzamide
  • Step 5 of Example 1 was repeated except for using the compound obtained in Step 6 in Example 124 as a starting material to obtain the title compound.
  • Example 125 N-(3-((4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methylphenyl)-3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzamide
  • Step 3 of Example 124 was repeated except for using 2-iodo-1-methyl-4-nitrobenzene (TCI Laboratory Chemicals, Cat. # I0706, CAS [7745-92-8]) instead of 3-iodo-4-methyl benzoate to obtain the product and then the procedure of Steps 1 to 3 of Example 4 was repeated using the product to obtain the title compound.
  • 2-iodo-1-methyl-4-nitrobenzene TCI Laboratory Chemicals, Cat. # I0706, CAS [7745-92-8]
  • Example 126 3-((4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-((4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methylbenzoic acid obtained in Step 6 of Example 124 and (4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)aniline to obtain the title compound.
  • Example 127 3-((4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-N-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-((4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methylbenzoic acid obtained in Step 6 of Example 124 and (4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)aniline to obtain the title compound.
  • Example 128 3-((4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methyl-N-(4-(1-methylpiperazine-1-yloxy)-3-(trifluoromethyl)phenyl)benzamide
  • Step 5 of Example 1 The procedure of Step 5 of Example 1 was repeated except for using 3-((4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-yl)ethynyl)-4-methylbenzoic acid obtained in Step 6 of Example 124 and 4-(1-methylpiperidine-4-yloxy)-3-(trifluoromethyl)aniline to obtain the title compound.
  • Table 1 The structures, NMR and MS m/z data of the compounds obtained in Examples 1 to 128 are summarized in Table 1 .
  • Table 1 Example No. Structure NMR and/or MS m/z Chemical name 1 MS m/z [M+1] 455.20 (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide 2 MS m/z [M+1] 582.23.
  • Test 1 Kinase activation assay (IC 50 )
  • a kinase domain comprising the entire cytoplasmic sequences of Bcr-Abl wt and Bcr-Abl T3151 mutation kinases and a tyrosine kinase assay kit (Panvera, P2837) were used to measure an inhibitory activation on Bcr-abl.
  • Other kinases such as FGFR, Flt, KDR, PDGFR, Fms, Kit, Raf, Tie2, Src, and Ret were also measured by the same method.
  • the each compound obtained in Examples 1 to 128 was diluted 10 times with a kinase buffer to a concentration of 10 ⁇ 0.0001 ⁇ M.
  • the each kinase was dilluted with a kinase buffer to a concentration of 30 ⁇ 300ng/assay by using the each Kd value.
  • the kinase buffer consisted of 100mM HEPES (PH 7.4), 25mM MgCl 2 , 10mM MnCl 2 , and 250 ⁇ M Na 3 VO 4 , being kept refrigerated after filtered.
  • the test was conducted in 96 well polystyrene round bottom plates. First, 10 ⁇ L of the diluted sample was combined with 10 ⁇ L of the enzyme solution at room temperature for 10 minutes using a shaker. 10 ⁇ L of Poly (Glu, Tyr) 4:1 (Sigma) matrix solution in an appropriate concentration and 10 ⁇ L of ATP solution (5 ⁇ 300 ⁇ M) were added to the sample and subjected to a reaction at room temperature for 60 minutes in a shaker. After 60 minutes, an EDTA solution was added thereto to complete the kinase reaction and the reaction mixture was left in a shaker for 5 minutes at room temperature.
  • a tracer, an antibody, and a fluorescence polarization (FP) diluted reaction solution were mixed at a ratio of 1:1:3 to prepare a detecting solution, 50 ⁇ L of which was added to the each sample and subjected to a reaction at room temperature for 30 minutes in a shaker.
  • a detecting solution 50 ⁇ L of which was added to the each sample and subjected to a reaction at room temperature for 30 minutes in a shaker.
  • the inventive compounds have excellent inhibitory activity on Bcr-Abl wt and Bcr-Abl T3151 kinases.
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